Ulcerative Dermatitis in C57BL/6 Mice

Ulcerative dermatitis (UD) is a common condition in C57BL/6 mice that is poorly understood and challenging to treat. Inconsistently there have been reports of an increased incidence of the disease in female mice, mice exposed to certain diets, mice of advanced age, and in several seasons. These inconsistencies indicated a need for a systematic review to better assess the evidence for commonly cited UD risk factors and treatments. The aims for the systematic review were to assess the quality of evidence for both: 1) commonly cited risk factors for UD, specifically sex, age, season, and diet; and 2) reported UD treatments. A search of three electronic databases was performed and articles were evaluated using previously published criteria for assessing methodological quality. Dietary factors, particularly caloric restriction, appear to have an effect on UD risk. Female sex was associated with an increased risk of UD in some studies, particularly diet studies, but not in others. Also, UD was seen most commonly in mice between 14 and 24 months of age in the studies reviewed. The role of season was not assessed in any of the articles that met the inclusion criteria. Of the three publications that evaluated UD treatments only one had an untreated or alternative therapy control. Further research is needed to explore epidemiologic aspects of UD and to compare treatment options. While early investigations into UD focused on the possibility of a primary dermatopathology (e.g. vasculitis of cutaneous vessels or follicular dysplasia) several recent studies have advocated scratching behavior as a primary driver for UD. The aim of the second study was to assess whether B6 mice demonstrate excessive scratching behavior under resting conditions or when provoked by epidermal barrier disruption compared to DBA/2, BALB/c, and ICR mice. The behavior of the mice was videotaped in observation chambers and reviewed for scratching frequency and duration both prior to and following tape stripping to initiate epidermal barrier injury. In addition, a spray test was performed as this test was previously associated with future UD development in B6 mice. In contrast to the hypothesis, the B6 mice did not scratch significantly more frequently, they did not have more long duration scratching events, and they did not have a higher median scratching duration for the long scratching events. In fact, the B6 mice showed the least scratching frequency and duration under many conditions. B6 mice demonstrated a statistically significant increase in scratching behavior following epidermal barrier disruption but the increased scratching did not surpass the rate or duration of scratching seen in the other genotypes of mice tested. Although the experimental results failed to support the hypothesis, the low scratching frequency and duration of B6 mice has interesting implications for the role of scratching in UD development

Loss of TRP53 (p53) accelerates tumorigenesis and changes the tumor spectrum of SJL/J mice.

Known as the guardian of the genome, transformation-related protein 53 (TRP53) is a well -known tumor suppressor. Here, we describe a novel TRP53 deficient mouse model on a tumor prone background-SJL/J mice. The absence of TRP53 (TRP53 nullizygosity) leads to a shift in the tumor spectrum from a non-Hodgkin\u27s-like disease to thymic lymphomas and testicular teratomas at a very rapid tumor onset averaging ~12 weeks of age. In haplotype studies, comparing tumor prone versus tumor resistant Trp53 null mouse strains, we found that other tumor suppressor, DNA repair and/or immune system genes modulate tumor incidence in TRP53 null strains, suggesting that even a strong tumor suppressor such as TRP53 is modulated by genetic background. Due to their rapid development of tumors, the SJL/J TRP53 null mice generated here can be used as an efficient chemotherapy or immunotherapy screening mouse model

Inter-comparison of Radio-Loudness Criteria for Type 1 AGNs in the XMM-COSMOS Survey

Limited studies have been performed on the radio-loud fraction in X-ray selected type 1 AGN samples. The consistency between various radio-loudness definitions also needs to be checked. We measure the radio-loudness of the 407 type 1 AGNs in the XMM-COSMOS quasar sample using nine criteria from the literature (six defined in the rest-frame and three defined in the observed frame): $R_L=\log(L_{5GHz}/L_B)$, $q_{24}=\log(L_{24\mu m}/L_{1.4GHz})$, $R_{uv}=\log(L_{5GHz}/L_{2500\AA})$, $R_{i}=\log(L_{1.4GHz}/L_i)$, $R_X=\log(\nu L_{\nu}(5GHz)/L_X)$, $P_{5GHz}=\log(P_{5GHz}(W/Hz/Sr))$, $R_{L,obs}=\log(f_{1.4GHz}/f_B)$ (observed frame), $R_{i,obs}=\log(f_{1.4GHz}/f_i)$ (observed frame), and $q_{24, obs}=\log(f_{24\mu m}/f_{1.4GHz})$ (observed frame). Using any single criterion defined in the rest-frame, we find a low radio-loud fraction of $\lesssim 5\%$ in the XMM-COSMOS type 1 AGN sample, except for $R_{uv}$. Requiring that any two criteria agree reduces the radio-loud fraction to $\lesssim 2\%$ for about 3/4 of the cases. The low radio-loud fraction cannot be simply explained by the contribution of the host galaxy luminosity and reddening. The $P_{5GHz}=\log(P_{5GHz}(W/Hz/Sr))$ gives the smallest radio-loud fraction. Two of the three radio-loud fractions from the criteria defined in the observed frame without k-correction ($R_{L,obs}$ and $R_{i,obs}$) are much larger than the radio-loud fractions from other criteria.Comment: 12 pages, 7 figures, MNRAS submitte

PPAR? Downregulation by TGF in Fibroblast and Impaired Expression and Function in Systemic Sclerosis: A Novel Mechanism for Progressive Fibrogenesis

The nuclear orphan receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) is expressed in multiple cell types in addition to adipocytes. Upon its activation by natural ligands such as fatty acids and eicosanoids, or by synthetic agonists such as rosiglitazone, PPAR-γ regulates adipogenesis, glucose uptake and inflammatory responses. Recent studies establish a novel role for PPAR-γ signaling as an endogenous mechanism for regulating transforming growth factor-ß (TGF-ß)- dependent fibrogenesis. Here, we sought to characterize PPAR-γ function in the prototypic fibrosing disorder systemic sclerosis (SSc), and delineate the factors governing PPAR-γ expression. We report that PPAR-γ levels were markedly diminished in skin and lung biopsies from patients with SSc, and in fibroblasts explanted from the lesional skin. In normal fibroblasts, treatment with TGF-ß resulted in a time- and dose-dependent down-regulation of PPAR-γ expression. Inhibition occurred at the transcriptional level and was mediated via canonical Smad signal transduction. Genome-wide expression profiling of SSc skin biopsies revealed a marked attenuation of PPAR-γ levels and transcriptional activity in a subset of patients with diffuse cutaneous SSc, which was correlated with the presence of a ''TGF-ß responsive gene signature'' in these biopsies. Together, these results demonstrate that the expression and function of PPAR-γ are impaired in SSc, and reveal the existence of a reciprocal inhibitory cross-talk between TGF-ß activation and PPAR-γ signaling in the context of fibrogenesis. In light of the potent anti-fibrotic effects attributed to PPAR-γ, these observations lead us to propose that excessive TGF-ß activity in SSc accounts for impaired PPAR-γ function, which in turn contributes to unchecked fibroblast activation and progressive fibrosis. © 2010 Wei et al

Egr-1 Induces a Profibrotic Injury/Repair Gene Program Associated with Systemic Sclerosis

Transforming growth factor-ß (TGF-ß) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-ß responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast “Egr-1-responsive gene signature” comprising over 600 genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived “Egr-1-responsive gene signature” was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the “Egr-1 responsive gene signature” was substantially enriched in the “diffuse-proliferation” subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the “inflammatory” intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-ß. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets

Cross-sectional associations between multiple lifestyle behaviors and health-related quality of life in the 10,000 steps cohort

Background: The independent and combined influence of smoking, alcohol consumption, physical activity, diet, sitting time, and sleep duration and quality on health status is not routinely examined. This study investigates the relationships between these lifestyle behaviors, independently and in combination, and health-related quality of life (HRQOL). Methods: Adult members of the 10,000 Steps project (n = 159,699) were invited to participate in an online survey in November-December 2011. Participant socio-demographics, lifestyle behaviors, and HRQOL (poor self-rated health; frequent unhealthy days) were assessed by self-report. The combined influence of poor lifestyle behaviors were examined, independently and also as part of two lifestyle behavior indices, one excluding sleep quality (Index 1) and one including sleep quality (Index 2). Adjusted Cox proportional hazard models were used to examine relationships between lifestyle behaviors and HRQOL. Results: A total of 10,478 participants provided complete data for the current study. For Index 1, the Prevalence Ratio (p value) of poor self-rated health was 1.54 (p = 0.001), 2.07 (p≤0.001), 3.00 (p≤0.001), 3.61 (p≤0.001) and 3.89 (p≤0.001) for people reporting two, three, four, five and six poor lifestyle behaviors, compared to people with 0-1 poor lifestyle behaviors. For Index 2, the Prevalence Ratio (p value) of poor self-rated health was 2.26 (p = 0.007), 3.29 (p≤0.001), 4.68 (p≤0.001), 6.48 (p≤0.001), 7.91 (p≤0.001) and 8.55 (p≤0.001) for people reporting two, three, four, five, six and seven poor lifestyle behaviors, compared to people with 0-1 poor lifestyle behaviors. Associations between the combined lifestyle behavior index and frequent unhealthy days were statistically significant and similar to those observed for poor self-rated health. Conclusions: Engaging in a greater number of poor lifestyle behaviors was associated with a higher prevalence of poor HRQOL. This association was exacerbated when sleep quality was included in the index. © 2014 Duncan et al

ST2 and IL-33 in Pregnancy and Pre-Eclampsia

Normal pregnancy is associated with a mild systemic inflammatory response and an immune bias towards type 2 cytokine production, whereas pre-eclampsia is characterized by a more intense inflammatory response, associated with endothelial dysfunction and a type 1 cytokine dominance. Interleukin (IL)-33 is a newly described member of the IL-1 family, which binds its receptor ST2L to induce type 2 cytokines. A soluble variant of ST2 (sST2) acts as a decoy receptor to regulate the activity of IL-33. In this study circulating IL-33 and sST2 were measured in each trimester of normal pregnancy and in women with pre-eclampsia. While IL-33 did not change throughout normal pregnancy, or between non-pregnant, normal pregnant or pre-eclamptic women, sST2 was significantly altered. sST2 was increased in the third trimester of normal pregnancy (p<0.001) and was further increased in pre-eclampsia (p<0.001). This increase was seen prior to the onset of disease (p<0.01). Pre-eclampsia is a disease caused by placental derived factors, and we show that IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas. ST2, but not IL-33, was identified on the syncytiotrophoblast layer, whereas IL-33 was expressed on perivascular tissue. In an in vitro placental perfusion model, sST2 was secreted by the placenta into the ‘maternal’ eluate, and placental explants treated with pro-inflammatory cytokines or subjected to hypoxia/reperfusion injury release more sST2, suggesting the origin of at least some of the increased amounts of circulating sST2 in pre-eclamptic women is the placenta. These results suggest that sST2 may play a significant role in pregnancies complicated by pre-eclampsia and increased sST2 could contribute to the type 1 bias seen in this disorder

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies